Metabolites involved in purine degradation, insulin resistance, and fatty acid oxidation are associated with prediction of Gestational diabetes in plasma

Abstract

Introduction Gestational diabetes mellitus (GDM) significantly increases maternal and fetal health risks, but factors predictive of GDM are poorly understood. Objectives Plasma metabolomics analyses were conducted in early pregnancy to identify potential metabolites associated with prediction of Gestational Diabetes Mellitus (GDM). Methods Sixty-eight pregnant women with overweight/obesity from a clinical trial of a lifestyle intervention were included. Participants who developed GDM (n=34; GDM group) were matched on treatment group, age, body mass index, and ethnicity with those who did not develop GDM (n=34; Non-GDM group). Blood draws were completed early in pregnancy (10-16 weeks). Plasma samples were analyzed by UPLC-MS using three metabolomics assays. Results One hundred thirty moieties were identified. Thirteen metabolites including pyrimidine/purine derivatives involved in uric acid metabolism, carboxylic acids, fatty acylcarnitines, and sphingomyelins (SM) were different when comparing the GDM vs. the Non-GDM groups (p<0.05). The most significant differences were elevations in the metabolites’ hypoxanthine, xanthine and alpha-hydroxybutyrate (p<0.002, adjusted p<0.02) in GDM patients. A panel consisting of four metabolites: SM 14:0, hypoxanthine, alpha-hydroxybutyrate, and xanthine presented the highest diagnostic accuracy with an AUC= 0.833 (95% CI: 0.572686-0.893946), classifying as a “very good panel”. Conclusion: Plasma metabolites mainly involved in purine degradation, insulin resistance, and fatty acid oxidation, were altered in early pregnancy in connection with subsequent GDM development.

Investigation of Metabolome Underlying the Biological Mechanisms of Acute Heat Stressed Granulosa Cells

“…The metabolite 16-hydroxyhexadecanoic acid, a long chain fatty acid, was downregulated. Xanthine and uridine, being the products of purine degradation [69,70], were downregulated in heat-stressed bGCs-indicating the upregulation of biochemical mechanisms involved in the salvage of purines [71]. The differential metabolite summary results confirm a low bioenergetics microenvironment and higher catabolic activity in response to heat stress.…”

Application of Metabolomics in Various Types of Diabetes

“…Changes in plasma metabolites involved in purine degradation, fatty acid oxidation, and IR during the early pregnancy are associated with the subsequent development of GDM. 78 In the first few years of diabetes onset, various metabolic disorders represented by AA dysregulation already existed and appeared in the early postpartum period of GDM. The properties of predicted metabolites take precedence over the results of some clinical parameters.…”

Predictive Gestational Diabetes Biomarkers With Sustained Alterations Throughout Pregnancy

“…The ketone body acetoacetate was elevated in 2 prediagnosis [ 21 , 22 ], 2 at-diagnosis studies [ 21 , 23 ], and 1 postdiagnosis study [ 24 ] indicating an increase in ketogenesis. In support of altered ketone body metabolism is the observed increase of β-hydroxybutyrate in 1 prediagnosis study [ 25 ], 2 at-diagnosis studies [ 21 , 26 ], and 1 postdiagnosis study [ 24 ]. Oleic acid, a monounsaturated fatty acid, was found to be elevated in 1 prediagnosis [ 27 ], 1 at-diagnosis [ 28 ], and 2 postdiagnosis studies [ 14 , 28 ], and the saturated fatty acid palmitic acid was elevated in 1 prediagnosis [ 14 ], 2 at-diagnosis [ 23 , 28 ], and 2 postdiagnosis studies [ 14 , 28 ].…”

“…In further support of dysregulated fatty acid metabolism is the observed alterations in alpha-hydroxybutyrate, a metabolite closely connected to FAO. Alpha-hydroxybutyrate was elevated in 1 prediagnosis [ 25 ], 3 at-diagnosis [ 23 , 26 , 28 ], and 1 postdiagnosis studies [ 15 ] ( Table 1 ). Alpha-hydroxybutyrate has been identified as a marker of the elevated ratio of cytosolic NADH/NAD + , as this metabolite is formed from alpha-ketobutyrate in a reaction that can be catalyzed by lactate dehydrogenase when the cytosolic NADH/NAD + ratio is increased [ 49 , 50 ] ( Fig.…”

“…Alpha-hydroxybutyrate is associated with impaired glucose tolerance and insulin resistance in people with T2DM [ 51 ] and has been found to predict dysglycemia in nondiabetic populations [ 49 , 52 ]. It has also been proposed as a potential early biomarker of GDM [ 25 ]. The elevation of alpha-hydroxybutyrate throughout GDM-affected pregnancy indicates persistent insulin resistance and may be related to continued reliance on FAO throughout pregnancy, which increases the NADH/NAD + ratio.…”